Orexin-A and orexin-B have been identified as two orphan GPCR endogenous peptide ligands (neuropeptides) (T. Sakurai et al., Cell, vol. 92 (1998), p. 573-585). Mammal orexin-A comprises 33 amino acids and has two disulfide bonds while orexin-B comprises 28 amino acids. Neurons that produce such orexins are located in lateral hypothalamic area (LHA) and posterior hypothalamus, projecting to various areas of the brain (e.g., cerebral cortex, olfactory bulb, hippocampus, amygdala, septal region, diagonal band of Broca, bed nucleus of the stria terminals, thalamus, anterior and posterior hypothalamus, midbrain, brain stem and spinal cord) (T. Sakurai et al., Cell, vol. 92 (1998), p. 573-585; Y. Date et al., Proc. Natl. Acad. Sci. USA, vol. 96 (1999), p-748-753; L. de Lecea et al., Proc. Natl. Acad. Sci. USA, vol. 95 (1998), p-322-327; T. Nambu et al., Brain Res., vol. 827 (1999), p-243-260; C. Peyron et al., J. Neurosci., vol. 18 (1998), p-9996-10015). Projections of orexin-producing neurons to such widespread areas suggest that orexin as a neuropeptide is involved in various physiologic functions.
In mammals, two orexin receptor subtypes named orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R) have been identified (T. Sakurai et al., Cell, vol. 92 (1998), p. 573-585). As to these subtypes, OX2R is known to have generally the same level of binding affinity to both orexin-A and orexin-B whereas OX1R is known to have 100 to 1000 times higher binding affinity to orexin-A than to orexin-B. Thus, orexin-A should particularly be important as a physiologically active substance.
Orexin-A has also been reported to be involved, for example, in the control of awakening and eating behaviors (T. Sakurai et al., Cell, vol. 92 (1998), p. 573-585; R. M. Chemelli et al., Cell, vol. 98 (1999), p-437-451; J. J. Hagan et al., Proc. Natl. Acad. Sci. USA, vol. 96 (1999), p-10911-10916). Furthermore, recent reports mention its relationship with stress. For example, intracerebroventricular administration of orexin-A to a mouse increases various stress-like behaviors such as face washing, grooming, searching and burrowing (T. Ida et al., Biochem. Biophys. Res. Commun., vol. 270 (2000), p-318-323; T. Ida et al., Brain Res., vol. 821 (1999), p-526-529). Meanwhile, in relation with these various behaviors, various OX1R antagonists have also been reported (WO 99/9024; WO 99/58533; WO 00/47577; WO 00/47580; WO 00/47576; WO 01/96302; WO 02/44172; WO 03/51368; WO 03/51873; WO 03/37847; WO 03/41711; WO 03/32991; WO 03/2561; WO 03/2559; WO 02/90355; WO 02/89800; WO 02/51838; WO 01/68609).
Today, various anxiety factors existing in social environment surrounding individuals are acknowledged as a problem. Specifically, anxiety ranges from vague anxiety to specific anxiety, for example, anxiety from overwork and stress, anxiety about domestic and international situations, anxiety over the future such as severe employment prospects, anxiety associated with depression, and anxiety associated with anesthesia and operation in the medical field. In addition, there are anxieties resulting from autonomic dysfunctions such as neurosis anxiety caused by genetic factors. Such anxiety brings an abnormal sense of tension as well as rational symptoms such as sleep disorder. Thus, in order to selectively alleviate or eliminate such anxieties and tensions, various minor tranquilizers, namely anxiolytic drugs, have been used suitably.